1. Field of the Invention
The present invention relates to a process for preparing an optically active (-)9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[2,3-de]([1,4]-benzoxazine -6-carboxylic acid derivative ("pyridobenzoxazine carboxylic acid derivative") represented by the formula (I) or pharmaceutically acceptable salt thereof having an excellent antimicrobial activity. ##STR1##
wherein,
R.sub.1 represents hydrogen atom or lower alkyl group having 1 to 5 carbon atoms. PA1 X represents a halogen atom; PA1 Z represents a leaving group; PA1 Y represents an oxygen or a sulfur atom; PA1 R.sub.a represents --C(.dbd.O)--R.sub.2 [wherein R.sub.2 represents an alkyl group having 1 to 5 carbon atoms, phenyl group, substituted phenyl group, alkoxy group having 1 to 5 carbon atoms, cycloalkoxy group having 3 to 5 carbon atoms, phenoxy group, substituted phenoxy group, primary or secondary amine group or alkylthio group having 1 to 5 carbon atoms]; PA1 R.sub.b represents alkyl group having 1 to 5 carbon atoms, phenyl group or substituted phenyl group; PA1 R represents the same as Ra above or R.sub.b --NH--C(.dbd.Y)[wherein R.sub.b and Y represent the same above]; and, PA1 R.sub.1 represents hydrogen atom or alkyl group having 1 to 5 carbon atoms. PA1 X and R represent the same above. PA1 R.sub.a, R.sub.b, Z, and Y represent the same above. PA1 X and R represent the same above, PA1 X and R, represent the same above. PA1 R.sub.1, represents the same above. PA1 R and R.sub.1 represent the same above; and, PA1 M represents metal atom such as potassium and sodium.
2. Description of the Prior Art
A variety of optically active pyridobenzoxazine carboxylic acid derivatives have been prepared and used as active ingredients for antibiotic agents, since the compounds are known to possess higher antimicrobial activity and weaker toxicity than optically inactive racemic mixture(see: Drugs of the Future, 17 (2), 559-563 (1992)).
In general, optically active (-)pyridobenzoxazine carboxylic acid derivatives have been prepared in the art by the following two processes: the first one comprises a step of selective hydrolysis of (.+-.)7,8-fluoro-2,3-dihydro-3-acetoxymethyl-4H-[(1,4]-benzoxazine by hydrolase; and, the second one comprises a step of optical resolution of (.+-.)7,8-fluoro-2,3-dihydro-3-acetoxymethyl-4H-[1,4]-benzoxazine by chemical reagent (see: EP 206,283; Korean Pat. No. 60,571). However, those processes have several drawbacks as followings: 1) theoretically 50% of isomers are lost; 2) high-priced reagent for separation is used; and, 3) complicate process of 8 steps are accompanied, which is not suitable for industrial-scale mass production. To solve the said problems, a process has been developed to. prepare (-)isomer by racemizing (+)isomer obtained as a by-product during the said process (see: Japanese Patent Publication (Hei) 10-357910).
Further, processes for preparing optically active pyridobenzoxazine carboxylic acid derivatives are disclosed in U.S. Pat. Nos. 4,777,253 and 5,237,060 and Korean Pat. No. 125,115 as well. These prior arts suggest that optically active (-)pyridobenzoxazine carboxylic acid derivatives using optically active (L)-alaninol can be prepared without optical resolution, which is represented as the following reaction scheme: ##STR2##
As shown in the scheme above, a starting material of 4,5-difluorobenzoic acid derivative should be employed in the reaction, since fluorine atom among various halogen atoms is essentially required for the last step of substituting proper piperazine for 10-halogen atom. Though this process is improved in a sense that optical resolution step is not necessary, it has revealed a critical demerit that very expensive 4,5-difluorobenzoic acid derivative is required. On the other hand, it has been reported that relatively inexpensive 4-chloro-5-fluorobenzoic acid derivative, whose reactivity is lowered than 4,5-difluorobenzoic acid derivative, leads to substitution reaction at 9-fluorine atom rather than 10-fluorine atom in the last step (see: Chem. Pharm. Bull., 32, 4907-4913 (1984)).
Therefore, there are strong reasons for exploring and developing a process for preparing optically active (-)pyridobenzoxazine carboxylic acid derivative by employing a low-priced material in a simple and economical manner.